Enantioselective Synthesis of Oxazocines via MQ‐Phos Enabled Palladium‐Catalyzed Asymmetric Formal [4+4]‐Cycloadditions

Abstract Oxazocines are key structural intermediates in the synthesis of natural products and pharmaceutical molecules. However, the synthesis of oxazocines especially in a highly enantioselective manner, is a long‐standing formidable challenge due to unfavorable energetics involved in cyclization. Herein, a series of new PNP‐Ligand P‐chiral stereocenter is first designed and synthesized, called MQ‐Phos, and successfully applied it in the Pd‐catalyzed enantioselective higher‐order formal [4+4]‐cycloaddition of α, β‐unsaturated imines with 2‐(hydroxymethyl)‐1‐arylallyl carbonates. The reaction features mild conditions, excellent regio‐ and enantiocontrol and a broad substrate scope (54 examples). Various medium‐sized rings can be afforded in moderate to excellent yields (up to 92%) and excellent enantioselectivity (up to 99% ee). The newly developed MQ‐Phos is critical for synthesis of the medium‐sized ring in excellent catalytic reactivity and enantioselectivity.


DOI: 10.1002/advs.202402170
Nefopam (nonopioid analgesic drug), Otonecine (hepatotoxic activity), ML341 (trypanocidal activity), and bremazocine (ĸ-opioid receptor (KOR) agonists). [2]At present, the available strategies for the synthesis of medium-sized rings mainly include intramolecular cyclization, intermolecular higher-order cycloaddition, multicomponent cyclization, and ring expansion.However, due to the presence of competitive reaction pathways and low levels of site-and stereoselectivity, the development of a general, efficient access to medium-sized rings by chemical synthesis, particularly in an asymmetric catalytic manner is quite challenging.Pd-trimethylenemethane (TMM) cycloaddition reactions have evolved into a versatile tool for the construction of carbo-and heterocycles with rich stereochemistry. [3]In the field, various zwitterion precursors that contain different nucleophilic moieties have been developed by Trost,[4] Chen, [5] Zi, [6] Guo, [7] Deng, [8] Li, [9] and other groups in the past decades.However, almost all these reactions depend on the non-substituted alkyl carbonates as zwitterion precursors, and the substitution patterns of the TMM moiety are relative underuse (Scheme 1a).As early as 1971, Faller explained the reason: when an extra 2-alkyl group was introduced to allylic substrates, both the syn-and the anti-isomer existed in solutions of certain 1, 2-disubstituted--allylmetal complexes. [10]ue to steric repulsion between the R 1 and R' groups of 1, 2-disubstituted--allylmetal complexes, the energy difference between its syn and anti isomer became smaller.Moreover, a challenging dynamic kinetic asymmetric transformation process was presented after the introduction of the 2-R' group.Besides, the regioselectiviy of the three different reactive sites on the Pd-allyl intermediate and resultant the problem of Z/E control also made it more difficult to get high efficiency and stereoselectivity (Scheme 1b). [11]To the best of our knowledge, the only successful example was realized by Chen and coworkers through a new double activation mode combining an achiral palladium complex and a chiral ammonium halide as an ion-pair catalyst, enabling the asymmetric [4+2] annulations of MBH adducts with diverse activated alkenes (Scheme 1c). [12]Recently, Lu, [13] Shibata [14] and Huang [15] respectively reported Pd-catalyzed enantio-, diastereo-, and regioselective [4+2] cycloadditions by using substituted-2-alkylidenetrimethylene carbonates.However, due to the unfavorable transannular interactions and entropic factors, these achievements are largely limited to the construction of five-or six-membered rings, the synthesis of enantioenriched medium-sized rings through asymmetric higher-order cycloaddition remains rare in the literature.Thus the development of new efficient catalyst systems and allylic precursors for the preparation of medium-sized rings is highly desired.
Li group has been devoted to the development of new P-chiral ligands derived from 1-phosphanorbornenes and apply them to metal-catalyzed asymmetric cycloadditions. [16]Their excellent regio-, chemo-and stereo-control ability prompt us to investigate the more challenging asymmetric high-order cycloaddition of 1, 2-disubstituted--allyl precursors with , -unsaturated imines.To achieve this goal, we selected tert-butyl (2-(hydroxymethyl)−1arylallyl) carbonates as 1, 2-disubstituted--allyl precursors to produce the optically active substituted oxazocines.However, several challenges would be encountered in this scenario: 1) tertbutyl (2-(hydroxymethyl)−1-arylallyl) carbonates were obtained in <8% yields by using the known methods. [17]Thus a new synthesis path should be explored to give higher yield.2) The second challenging part was finding ideal ligands for the construction of oxazocines with complete Z/E selectivity, b/l selectivity, and high enantioselectivity.As far as we know, the synthesis of target chiral oxazocines could not be achieved by the asymmetric high-order cycloaddition reactions using the corresponding tertbutyl (2-(hydroxymethyl)−1-arylallyl) or the chiral catalysts based on known chiral ligands, which demonstrated the uniqueness of this strategy.3) In most cases, the substrate scope was quite limited for the synthesis of medium-sized rings.To circumvent these issues, we first designed an intramolecular ester exchange strategy to form the tert-butyl (2-(hydroxymethyl)−1-arylallyl) carbonates (see Supporting Information in detail), which were obtained in 44-76% yields (Scheme 1d).Second, we designed a kind of new chiral PNP-ligands based on 1-phosphanorbornenes and (9, 9-dimethyl-9H-xanthen-4-yl)diphenylphosphane (MQ-Phos), which could be used in highly regio-and enantioselective highorder cycloaddition of 1, 2-disubstituted allylic carbonates.Chiral oxazocines could be obtained in up to 92% yield with >20:1 branched/linear (b/l) ratio, >20:1 Z/E ratio and 99% ee (Scheme 1e).

Results and Discussion
Initially, we employed N-((1E, 2E)−1, 3diphenylallylidene)benzenesulfonamide 1 and tert-butyl (2-(hydroxymethyl)−1-phenylallyl) carbonate 2 as model substrates to investigate various chiral ligands (Scheme 2), bases, palladium sources, solvents, and run the reactions at different temperatures.First, different representative ligands (L1-L7) were tested, most of them could not produce the desired product 3, and only ligand L2 was able to give the product in 6% yield with 18% ee, which confirmed the less reactivity of racemic 1, 2-disubstituted allylic products.Next, GF-Phos, which performed well in palladium-catalyzed allylation, was used as a chiral ligand, unfortunately, only trace product 3 was obtained. [18]Thus we checked the efficiency of a series of ZD-Phos ligands that we developed.Using Gan-Phos, Jia-Phos, and Yue-Phos as the chiral ligand did not furnish satisfactory results.When Meng-Phos was tested in toluene at rt, to our delight, the desired product 3 was obtained in 83% yield with 92% ee, while Pd/Meng-Phos complex showed poor substrate tolerance, only a handful of products 3 were obtained with high enantioselectivity.It was possible that extremely twisted conformations of eight-member cycle resulted in the difficulty in stereocontrol.Thus we tested our newly designed chiral ligands MQ-Phos and discovered MQ-Phos, which was able to achieve a higher yield and excellent ee (74% yield, 93% ee), slightly higher yield was produced by appropriately raising the temperature (78% yield, 94% ee).The structure and configuration of MQ-Phos were unambiguously determined via X-ray diffraction analysis. [19]Interestingly, all MQ-Phos performed well in our palladium-catalyzed [4+4] cycloaddition, the desired product 3 was obtained in 41-78% yields with 91-96% ee.Overall consideration, we selected MQPhos-1 as the ligand to screen other conditions (See the Supporting Information (SI) in detail).Eventually, the optimal conditions for the reaction were identified as N-((1E, 2E)−1, 3-diphenylallylidene)benzenesulfonamide (1.0 equiv), tert-butyl (2-(hydroxymethyl)−1-phenylallyl) carbonate (2.0 equiv), Cs 2 CO 3 (2.0 equiv), Pd 2 (dba) 3 (5 mol%), MQPhos-1 (10 mol%), and toluene as the solvent at 40 °C (Scheme 2).
Under the optimal conditions in hand, the substituent effect on the aryl groups of different 1,2-disubstituted allyl carbonates was first investigated, which was often relatively less reactive than those unsubstituted 2-(hydroxymethyl)allyl) carbonate for the asymmetric cycloaddition.As outlined in Scheme 3, electrondonating, Electron-neutral, and electron-withdrawing groups could be tolerated at the ortho-, meta-, para-position of the allyl carbonates, the desired products 3-12 were obtained in 54-78% yields with 73-94% ee.Obviously, the substituent position of 1,2disubstituted allyl carbonates played the key role in the control of enantioselectivity, a high enantioselectivity was obtained when meta-position of the allyl carbonates was used in the reaction.The 1,2-disubstituted allyl carbonates were further examined, interestingly, the 1,2-disubstituted allyl carbonates with a small hin-dered methyl group reacted smoothly to give the corresponding oxazocine in 65% yield with 92% ee (13).Besides 2-naphthylsubstituted allylic carbonates was also a suitable substrate in this reaction to produce the product 14 in 56% yield with 93% ee (14).
We next turned to investigate the catalytic Pd-oxyallyl species with , -unsaturated imines under standard reaction conditions (Scheme 4).Usually, R 2 groups of , -unsaturated imines preformed predominantly in enantiomer control.And only specific R 2 groups of , -unsaturated imines could show well stereocontrol in asymmetric cycloaddition.Notably, a wide range of , -unsaturated imines with electronically varied R 2 substituents, such as 4-MeC 6 H 4 , 4-CF 3 C 6 H 4 , 4-MeOC 6 H 4 , 4-FC 6 H 4 , 4-ClC 6 H 4 , 4-BrC 6 H 4 , 2-BrC 6 H 4 and 3-BrC 6 H 4 , could readily participate in the [4+4]-cycloaddition, affording the corresponding oxazocines in 60-83% yields and with 90-98% ee (15, 16, 18-23).Even R 2 substituents of , -unsaturated imines were methyl and 2-thiethyl, The desired oxazocines were prepared with 80% and 92% yields, 87% and 90% ee respectively (17, 24).We next turned to investigate the R 3 substituents of , -unsaturated imines under standard reaction conditions.Notably, , -unsaturated imines with different R 3 substituents were applicable to the reaction, furnishing the corresponding products 25-33 with satisfactory outcomes.It was worth noting that ortho-position of R 3 of , -unsaturated imine was applied, only 77% ee was obtained, which might be due to steric hindrance.The , unsaturated imine with 3-thienyl could participate in the present cycloaddition to give enantioenriched oxazocine in 45% yield with 96% ee (34).Next, we turned to investigate the R 4 substituents of , -unsaturated imines.The cycloaddition was also readily scalable, The , -unsaturated imines with different R 4 aromatic motifs could all participate in the present cycloaddition to afford the desired oxazocines in 45-75% yields with 86→99% ee (35-47).In addition, the , -unsaturated imines with different R 3 and R 4 groups proceeded smoothly in the cycloaddition to give 52−63% yields of 48-55 with 90−95% ee.Unfortunately, when R 3 and R 4 were 4-Cl group, slightly lower yield and enantioselectivity were obtained (54).The , -unsaturated imines with different R 2 and R 4 groups proceeded smoothly in the cycloaddition to give 68% yields of 56 with 91% ee.The structure and configuration of 3 and 42 were unambiguously determined via X-ray diffraction analysis (See the Supporting Information (SI) in details). [20]o gain insights into the effect of E/Z allyl carbonates geometric isomers on the steric control of the reaction, other types of allyl carbonates were then carried out (Scheme 5). [21]When 2benzylidenetrimethylene carbonate 57, prepared by Hayashi, [22] was used as an allyl precursor, the desired 3 was obtained in 70% yield with 92% ee.Next, we chose allyl carbonates E-58 and Z-58 as allyl precursors, the [4+4]-cycloaddition proceeded smoothly to lead to 3 as the sole product in 48% and 56% yields with 88% and 91% ee, respectively.Even the mixed Z/E isomers 58 were Scheme 6. Synthetic transformations.used under the standard conditions, the desired oxazocine 3 as the sole product was still produced in 54% yield with 91% ee. [23]hese results suggested that Pd/MQ-Phos complex preformed excellent abilities in Z/E, b/l, and enantio-control.
To demonstrate the practicality of our approach, some further synthetic transformations of 3 were then carried out (Scheme 6).First, oxidation of 3 using K 2 OsO 4 •2H 2 O and NMO was studied, to our delight, the desired adduct 59 was obtained as a single diastereomer in 67% yield with 90% ee.Then, the halogenation of 3 led to the desired compound 60 in 66% yield with 87% ee.

Conclusion
In conclusion, we have developed a highly regio-, chemo-, and enantioselective palladium-catalyzed asymmetric high-order [4+4]-cycloaddition reaction of 1,2-disubstituted allylic carbonates with a variety of , -unsaturated imines, which provided an efficient method for the synthesis of oxazocine compounds.The salient features of the method include high efficiency, mild reaction conditions, simple operation, and excellent Z/E-, b/l, and enantioselectivity.A rationally designed MQ-Phos ligand played a critical role in the reaction efficiency and selectivity.Further studies including the allocation of MQ-Phos in asymmetric palladium catalysis, especially the tandem cycloaddition reactions are underway and will be reported in due course.